This project comprises biological and molecular studies of various replication competent, non-oncogene containing ecotropic and MCF-type recombinant murine leukemia viruses (MuLVs), and hybrid MuLVs constructed in vitro by exchange of genome components of viruses with differing properties. Viral pathogenesis is studied in depth following inoculation of selected mouse strains, by testing of mice by a variety of techniques for replication of input virus and generation of new recombinant viruses, histopathological and immunological characterization of tumors, and molecular study of tumors for new proviral integrations or rearrangements of cellular genes, or for expression of activated gene products. Of particular interest have been the ecotropic MuLVs isolated from California wild mice, viruses which can induce both a neurological disease and a variety of T-, B-, erythroid and myeloid cell neoplasms, and the MCF viruses recovered with high frequency from such tumors. In addition to delineating further the diverse disease inducing potential of the ecotropic viruses we have isolated and biologically characterized 3 new oncogene-containing viruses (2 representing transductions of activated mouse c-ras, and 1 containing an as yet unidentified oncogene), a highly lymphomagenic MCF virus which is helper-independent for both replication and induction of disease, and several other MCF viruses of potential interest. One of the ras-related viruses has been molecularly cloned and extensively characterized. Biologically active molecular clones have also been obtained for the lymphomagenic MCF virus and mapping and sequencing studies are in progress. Construction of hybrid virus genomes from portions of molecularly cloned viral DNAs has yielded viruses with altered pathogenic capacities. Efforts have concentrated on determining the genome segment(s) controlling target cell specificity as manifested by virus recovery and nature of the disease induced. These studies indicate major roles for the LTR region, specifically putative enhancer sequences in U3, in Friend MuLV-induced erythroleukemia and Moloney MuLV induced lymphoblastic lymphoma; and for LTR plus gp70, Prp15, and gag coding sequences in the case of AKR 247 MCF MuLV thymic lymphomagenesis.